Journal article
Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation
The Journal of neuroscience, v 31(17), pp 6605-6615
27 Apr 2011
PMID: 21525301
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5-HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5-HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5-HT transport, requires significantly higher Na
+
and Cl
−
concentrations to sustain transport, is inhibited noncompetitively by 5-HT, and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors. We use a thiol-reactive methane thiosulfonate (MTS) reagent to modify a conformationally sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5-HT. Cotransfection of an inactive or an MTS-sensitive SERT with wild-type SERT subunits reveals an absence of cooperative interactions between subunits during DA but not 5-HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show using
in vivo
high-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporter
in vivo
and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT.
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Details
- Title
- Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation
- Creators
- Mads Breum Larsen - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260Mark S Sonders - Center for Molecular Recognition, Columbia University and New York State Psychiatric Institute, New York, New York 10032, andOle Valente Mortensen - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260Gaynor A Larson - Department of Pharmacology, University of Colorado Denver, Aurora, Colorado 80045Nancy R Zahniser - Department of Pharmacology, University of Colorado Denver, Aurora, Colorado 80045Susan G Amara - Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260
- Publication Details
- The Journal of neuroscience, v 31(17), pp 6605-6615
- Publisher
- Society for Neuroscience
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000289934600037
- Scopus ID
- 2-s2.0-79955769299
- Other Identifier
- 991014878246904721
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InCites Highlights
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences